The Mx system of mammals comprises a family of interferon alpha/beta inducible cellular proteins, one of which, the Mx1 protein of mice, is involved in protection against influenza. Evidence that this protein is a crucial factor determining death or survival of a laboratory mouse after experimental infection in vivo is based on the observation that of all inbred mice, only those belonging to strain A2G and SL/NiA survive influenza infection, and that only mice of these strains contain in their genome the Mx+ allele which codes for the Mx1 protein. Mice of other strains contain either one of two Mx- alleles (with a coding capacity for only truncated Mx1 proteins), and they succumb to infection. In appropriate breeding experiments, the Mx+ allele segregates with resistance to influenza, indicating that this allele is the predominant gene controlling pathogenesis of experimental influenza infection in mice. The biofunction of Mx proteins of other mammalian species including humans is less clear. A classical genetic analysis of the Mx system in these species is not feasible at present since mutant individuals not expressing corresponding Mx proteins have yet to be found. To assess the role of the Mx proteins of these species, four different approaches have been chosen. First, we are microinjecting specific anti-Mx antibodies into interferon-treated cells, and are testing these injected cells for susceptibility to influenza infection. Second, we a re expressing various Mx cDNAs under appropriate promoters in Mx- mouse cells and are testing these cells likewise for influenza susceptibility. Third, we are purifying Mx proteins and are testing their biofunction after injection into cells. Fourth, we are expressing Mx proteins in transgenic mice and are testing these mice for influenza susceptibility. Available data indicate that the Mx system of mice and rats is highly active against influenza virus but that the Mx system of man is less active. Current research focuses on a detailed analysis of the mechanisms of virus inhibition, and on the question of how to boost the Mx system in those species in which it displays a lower activity.